Reduced-Intensity Stem Cell Transplantation Is a Promising Therapeutic Strategy for Pediatric Patients with Wiskott-Aldrich Syndrome: A Case Series of 7 Patients with a Uniform Reduced-Intensity Conditioning

Wiskott-Aldrich syndrome (WAS) is a life-threatening X-linked disorder characterized by thrombocytopenia, eczema, and immunodeficiency, and it affects individuals who also have an increased risk of lymphomas and autoimmunity. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for primary immunodeficiency such as WAS. However, conventional myeloablative regimens cause early toxicity and long-term morbidity such as growth retardation, infertility and learning disabilities. Recently, to relieve these toxicities, reduced-intensity conditioning (RIC) regimens have been used for children with primary immunodeficiency. However, there are no detailed case series reports of WAS patients receiving allogeneic HSCT with a uniform RIC regimen. We report here a successful series of 7 patients and evaluate the efficacy and safety of RIC for the treatment of WAS.

Patients and methods: Seven children with WAS received HSCT following RIC at Saitama Children's Medical Center or The University of Tokyo Hospital from August 2004 to February 2011. They included three pairs of brothers. The median age at diagnosis was 1 (range, 0–17 months) month and that at transplant was 14.5 (range, 8–27 months) months. Stem cell sources were bone marrow from HLA-matched unrelated donors in 6 patients, and unrelated cord blood (UCB) in 1 patient. The UCB unit had 4/6 HLA matches. The median total nucleated cell dose was 4.46×10⁸ (range, 1.32–7.79×10⁸)/kg. A uniform preparative regimen was used, consisting of fludarabine (180 mg/m² total dose), busulfan (8–10 mg/kg total dose) and anti-thymocyte globulin (horse anti-thymocyte globulin 10 mg/kgx4 doses or rabbit anti-thymocyte globulin 1.25–2.5 mg/kgx4 doses). One of the patients additionally received 3 Gy total body irradiation (TBI) because the stem cell source was HLA-mismatched UCB. Prophylaxis for graft-versus-host disease (GVHD) was performed using tacrolimus and short-term methotrexate in all patients. We retrospectively analyzed toxicity, GVHD, engraftment, WAS protein expression and immune reconstitution. The median duration of follow-up after transplant was 40 (range, 4–78 months) months.

All patients are alive and achieved engraftment. Neutrophil engraftment occurred in a median of 22 (range, 12–36 days) days and platelet engraftment occurred in a median of 21 (range, 13–45 days) days. Five patients achieved full chimerism (>95% donor chimerism) and 2 patients had mixed chimerism (5%-95% donor chimerism). These 2 patients had 30% and 27.7% donor chimerism in peripheral blood at 15 months and 6 months, respectively, after transplant. All patients showed WAS protein expression and increased platelet counts. However, 2 children with mixed chimerism still had thrombocytopenia without transfusion dependence. Neither acute GVHD more than grade II nor extensive chronic GVHD occurred. There was no treatment-related mortality. No severe infections were observed, except for 1 child who had Epstein-Barr virus associated with lymphoproliferative disorder and he received rituximab. He also required steroid treatment due to autoimmune cytopenia post HSCT. He had resolution of autoimmune hemolytic anemia and is currently off steroid treatment. He had mixed chimerism and persistent incomplete immune reconstitution at 16 months after HSCT. Four of 5 patients with evidence of engraftment more than 1 year after transplantation had normal CD3, CD4, and CD19 levels, CD4/CD8 ratio, immunoglobulin G levels and T-cell function as assessed by a lymphocyte blast transformation test induced by phytohemagglutinin.

All patients achieved engraftment and had disease resolution or stabilization with acceptable toxicities. Five of 7 patients achieved excellent donor chimerism. Persistent thrombocytopenia after HCT and autoimmunity were associated with mixed chimerism. Low dose TBI might be useful to achieve good donor engraftment when using a RIC regimen. This RIC regimen could achieve donor cell engraftment with less morbidity than conventional myeloablative regimens, which is an important consideration for patients who currently consider that the risks of conventional transplants are unacceptably high. Reduced-intensity stem cell transplantation is a promising treatment for patients with WAS. The efficacy of RIC as a less-toxic regimen should be tested prospectively in the future.

No relevant conflicts of interest to declare.